The long term goal of the proposed studies is to understand the signal transduction mechanisms in the development and functions of the cardiovascular system. The previous funding period focused on the role of focal adhesion kinase (FAK) in endothelial cells (ECs) in vasculogenesis and angiogenesis as well as in cardiac myocytes in heart development and function by using Cre-loxP mediated conditional knockout (KO) of FAK in ECs and cardiomyocytes. Analysis of the EC-specific FAK conditional KO mice established a critical role for FAK in angiogenesis and vascular development during embryogenesis in vivo. Furthermore, we showed that deletion of FAK in the isolated primary ECs led to multiple defects including reduced cell survival and migration which may be responsible for the defective angiogenesis and vascular development in vivo. Analysis of the cardiomyocyte-specific FAK conditional KO mice suggested a role of FAK in the regulation of cardiac hypertrophy. In addition, we generated a mouse KO for FIP200 (FAK-family interacting protein of 200 kDa) to understand its functions in vivo. We found that inactivation of FIP200 gene resulted in mid/late-gestational embryonic lethality caused by heart failure and liver lesions. Analysis of the FIP200 KO mice suggested that alterations in TSC-mTOR and TNFa signaling pathways leading to changes in cell size and apoptosis in the heart and liver may be responsible for the developmental abnormality and embryonic lethality in FIP200 KO mice. Despite the progress suggesting important functions of FAK and FIP200 in the cardiovascular development and functions, the role of specific signaling pathways regulated by FAK and FIP200 has not been examined in the context of cardiovascular development in vivo. Based on our previous and preliminary studies, we propose to 1.) analyze the FAK signaling pathways in the regulation of EC migration, invasion and angiogenesis using isolated primary ECs, 2.) determine the role of FAK signaling pathways in angiogenesis and vascular development in vivo by using mouse knock-in approaches, and 3.) investigate the mechanisms of FIP200 regulation of TSC-mTOR and TNFa signaling pathways in cardiac development using a combination of cell and molecular biology approaches in isolated cardiomyocytes and genetic interaction studies of various relevant KO mice. Relevance: These studies will generate significant insights into the mechanisms of signal transduction by FAK and FIP200 in the cardiovascular system in vivo and may also provide critical information for potential development of novel therapies for cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073394-08
Application #
7781368
Study Section
Intercellular Interactions (ICI)
Program Officer
Schramm, Charlene A
Project Start
2003-04-08
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
8
Fiscal Year
2010
Total Cost
$372,200
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chen, Song; Wang, Chenran; Yeo, Syn et al. (2016) Distinct roles of autophagy-dependent and -independent functions of FIP200 revealed by generation and analysis of a mutant knock-in mouse model. Genes Dev 30:856-69
Wang, Chenran; Chen, Song; Yeo, Syn et al. (2016) Elevated p62/SQSTM1 determines the fate of autophagy-deficient neural stem cells by increasing superoxide. J Cell Biol 212:545-60
Sun, Shaogang; Chen, Song; Liu, Fei et al. (2015) Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling. Cancer Cell 28:758-772
Fang, Fang; Sun, Shaogang; Wang, Li et al. (2015) Neural Crest-Specific TSC1 Deletion in Mice Leads to Sclerotic Craniofacial Bone Lesion. J Bone Miner Res 30:1195-205
Chen, Xiao Lei; Nam, Ju-Ock; Jean, Christine et al. (2012) VEGF-induced vascular permeability is mediated by FAK. Dev Cell 22:146-57
Fan, Huaping; Guan, Jun-Lin (2011) Compensatory function of Pyk2 protein in the promotion of focal adhesion kinase (FAK)-null mammary cancer stem cell tumorigenicity and metastatic activity. J Biol Chem 286:18573-82
Zhao, Xiaofeng; Guan, Jun-Lin (2011) Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliv Rev 63:610-5
Peng, Xu; Guan, Jun-Lin (2011) Focal adhesion kinase: from in vitro studies to functional analyses in vivo. Curr Protein Pept Sci 12:52-67
Li, Xiao-Yan; Zhou, Xiaoming; Rowe, R Grant et al. (2011) Snail1 controls epithelial-mesenchymal lineage commitment in focal adhesion kinase-null embryonic cells. J Cell Biol 195:729-38
Wang, Chenran; Yoo, Youngdong; Fan, Huaping et al. (2010) Regulation of Integrin ? 1 recycling to lipid rafts by Rab1a to promote cell migration. J Biol Chem 285:29398-405

Showing the most recent 10 out of 26 publications